Autoimmune Renal Calcium and Magnesium Wasting
Authors: Karl P. Schlingmann, Martin Konrad
Journal: Journal of the American Society of Nephrology (2022)

Integrated Discussion Rare monogenic disorders affecting the kidney are commonly considered a domain of the pediatric rather than the adult nephrologist. That this simple assumption falls short is illustrated by an increasing number of patients with rare inherited disorders diagnosed during infancy or childhood who now reach adult age, and by patients who are diagnosed late in adolescence or adulthood with an "atypical" or milder clinical course. In order to decipher and diagnose a yet unidentified rare disease, physicians and researchers have to rely on an in-depth study of a small cohort of affected individuals or even of a single patient. Unfortunately, multi-omic approaches are increasingly replacing thorough clinical evaluation and judgment rather than complementing hypothesis-driven targeted laboratory studies. The study by Figueres and colleagues is a beautiful example of successful workup of a single adult patient who unexpectedly presented with symptomatic combined renal calcium and magnesium wasting and a deterioration of kidney function.1 The clinical picture was highly reminiscent of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)—a rare autosomal recessive disease caused by mutations in the genes encoding renal tubular tight junction proteins claudin-16 or claudin-19.2 Both claudins are part of a complex tight junction network in the thick ascending limb of Henle's loop, with a mosaic expression of different claudins and spatially separated ion permeabilities.3 Within this network, claudin-16 and -19 are thought to form a paracellular pore that is highly permeable for magnesium. The expression pattern of different claudins within the tight junction network, and thus paracellular calcium and magnesium reabsorption, are regulated by the basolateral calcium-sensing receptor and the PTH1 receptor.2 These receptors critically influence not only tight junction composition but also transcellular salt reabsorption rates as a prerequisite for the generation of transepithelial potential and passive paracellular ion fluxes. FHHNC patients typically present at young ages with symptomatic hypomagnesemia, nephrocalcinosis or kidney stones, and urinary tract infections. Most importantly, they typically progress to ESKD in adolescence or early adulthood. In fact, genetic screening excluded a hereditary basis of the FHHNC phenotype in the patient Figueres and colleagues studied. Rather, the presence of tubulointerstitial nephritis in the patient's kidney biopsy prompted the authors to investigate an autoimmune basis of the disease, which the discovery of specific claudin-16 autoantibodies finally confirmed. Not only were these autoantibodies in the patient's plasma or in the purified IgG fraction detected by immunofluorescence in the thick ascending limb segments of murine kidney, whereas they were absent in cldn16-ko mice, but they were also shown to induce renal magnesium wasting in vivo in rats. In the presented patient, immunosuppressive treatment, including plasma exchange and rituximab, ameliorated changes in calcium and magnesium metabolism and stabilized renal function. The most likely underlying cause of this autoimmunologic phenomenon was discovered years later when renal cell carcinoma was diagnosed with high tumor cell CLDN16 mRNA expression. Unfortunately, the neoplasia was fatal. Glomerular disorders mediated by immunologic processes are a well-established clinical entity in nephrology. The pathophysiology usually comprises either a deposition of immune complexes as in common forms of glomerulonephritis such as post-infectious glomerulonephritis or IgA nephropathy, or autoantibodies directed against glomerular antigens as seen in Goodpasture syndrome with anti-glomerular basement membrane antibodies. One of the most prominent examples in which knowledge of specific autoantibodies has revolutionized diagnosis and management is membranous nephropathy, with the discovery of anti-PLA2R and anti-THSD7A antibodies. Another example of a glomerular antigen involved in autoimmunity is nephrin—a major component of the slit diaphragm between podocyte foot processes as part of the filtration barrier. Besides nephrin's role in the Finnish type of congenital nephrotic syndrome, it was recently shown to be a target antigen for autoantibodies in patients with minimal change nephrotic syndrome.4 Moreover, nephrin autoantibodies have been discovered in patients with congenital nephrotic syndrome who do not express nephrin in their native kidneys after kidney transplantation.5 Immunologically mediated tubular disorders with specific disturbances in tubular water and electrolyte handling typically draw much less attention. However, similar autoimmunologic reactions as observed in glomerular disease also affect different components of the tubular epithelium and the renal interstitium. Classic anti-tubular basement membrane (TBM) disease is a rare disorder with interstitial nephritis, clinically characterized by polyuria/polydipsia, hematuria, proteinuria, and a varying degree of AKI. Kidney biopsy, in addition to a mixed interstitial infiltrate, tubulitis, and acute tubular injury, demonstrates a linear staining of TBMs for IgG on immunofluorescence. The targeted antigen, a glycoprotein located at the TBM of proximal tubules, was identified almost 40 years ago and cloned in 2000.6 The spectrum of tubular antigens that anti-tubular cell antibodies target is even more diverse, and the resulting clinical correlates reach well beyond pure tubulointerstitial nephritis and may mimic classic hereditary tubulopathies. Although a subset of studies specifically aimed to identify the respective antigens, other investigations inferred the presence of an autoantibody directed against a specific tubular antigen and the affected tubular segment from clinical phenotype and laboratory findings. As an example, renal tubular acidosis and impaired renal acidification capacity in patients with autoimmune disease could be attributed to autoantibodies against renal carboanhydrase (CA-II) in the cortical collecting duct.7 Similarly, a Gitelman syndrome–like tubulopathy with hypokalemia and hypomagnesemia has repeatedly been observed in patients with autoimmune disease that was diagnosed by thiazide test, confirmed by the detection of autoantibodies against sodium chloride cotransporter NCC (SLC12A3) in the distal convoluted tubule, and successfully treated with immunosuppression.8 Autoimmune central diabetes insipidus illustrates a tubulopathy in which the targeted antigen is not even in the kidney.9 Rabphilin-3A is a protein involved in membrane trafficking and exocytosis of secretory vesicles in pituitary neurons. The majority of autoimmune tubulopathies has been described in patients with systemic autoimmune disease, especially in patients with Sjögren syndrome.10 However, autoimmune kidney disease can also be part of a paraneoplastic syndrome in which tumor antigens induce the formation of autoantibodies targeting the native kidney. Indeed, Figueres and colleagues diagnosed a renal cell carcinoma in their patient during follow-up, with abundant and possibly exposed expression of claudin-16 in tumor cells. Retrospectively, the FHHNC-like picture not only reflected the initial clinical symptom of neoplasia, but also indicated a relapse of the disease with recurrence of hypomagnesemia and deterioration of renal function. The fascinating case report presented by Figueres and colleagues emphasizes the importance of differentiating between a hereditary or acquired etiology if a rare kidney disorder that typically manifests in childhood is diagnosed in an adult patient. Moreover, if an autoimmune phenomenon is suspected, an underlying immunologic disorder or the possibility of a paraneoplastic situation should be considered. The development of highly specific and sensitive autoantibody tests will hopefully help to identify autoimmune kidney disease at an early stage and allow for an appropriate therapy targeting the underlying pathology. Disclosures M. Konrad reports consultancy for Otsuka. The remaining author has nothing to disclose. Funding None.